JPH03163042A - Chalcone derivative - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (R<1> is 2- or 4-site-substituted 4-15C straight chain, branched or cyclic alkyl or 3-15C alkenyl; R<2> is H or 1-3C straight chain or branched alkyl; X is 1-3C straight chain or branched alkylene). EXAMPLE:2'-ethoxycarbonylmethoxy-4-n-hexyl-4'-(3-methyl-2-butenyloxy)c halcone. USE:A medicine having strong anti-ulcer activity, tunica mucosa ventriculi- protective effect and acid secretion-inhibitory effect each useful for the prevention and therapy for gastrointestinal inflammatory diseases, gastric ulcer, duodenal ulcer, etc. PREPARATION:A condensation is made between a compound of formula V and a second compound of formula III in the presence of an alkali into a new material of formula II, which is then reacted with a third compound of formula IV (R<3> is 1-3C alkyl; Y is Cl, Br, I or tosyl) followed by, if needed, hydrolysis, thus obtaining the objective compound of the formula I (formula VI, VII).

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a novel chalcone derivative in which the 2nd or 4th position of the chalcone skeleton is substituted with an alkyl group or an alkenyl group, and intermediates for producing the same, and more specifically, The present invention relates to novel chalcone derivatives and intermediates for producing the same, which have antiulcer effects, gastric mucosal protective effects, and acid secretion suppressing effects in the treatment of gastrointestinal diseases.

[Prior Art] Many compounds of chalcone derivatives are known both naturally and synthetically. Among them, carboxyalkoxycarfune derivatives are particularly well known in US Pat. , No. 305, etc., as a compound having antiulcer activity.

[Problems to be Solved by the Invention] Currently, in the treatment of gastric ulcers or duodenal ulcers, H, receptor antagonists are the main drug of choice due to their high cure rate and early alleviation of various symptoms. However, in drug therapy using H, receptor antagonists, serious problems remain to be solved, such as side effects such as hypergastrinemia and high frequency of recurrence after discontinuation of administration.

In order to solve these problems, it is necessary to develop a protective anti-ulcer agent that has strong anti-ulcer effects, protects the gastric mucosa, and suppresses acid secretion, so that it can be used as the first-line agent for ulcer treatment. desired.

[Means for Solving the Problems] The present inventors have discovered that a compound having an alkyl group or an alkenyl group having an appropriate number of carbon atoms at the 2- to 4-positions of a 2'-carpoxyalkoxychalcone is a known carboxyalfoxychalcone. It was discovered that it exhibits antiulcer effect, gastric mucosal protective effect, and acid secretion suppressing effect that are superior to derivatives, and as a result of further detailed study, the present invention was completed.

The present invention is based on the general formula (I) (wherein Rl is substituted at the 2- or 4-position and has 4 to 1 carbon atoms)
5 linear, branched, or cyclic alkyl group or 3 carbon atoms
~15 alkenyl groups, R! is a hydrogen atom, carbon number 1~
3 linear or branched alkyl group, X has 1 to 1 carbon atoms
3 represents a linear or branched alkylene group. ) is a chalcone derivative represented by

In the present invention, R' is a linear, branched, or cyclic alkyl group having 4 to 15 carbon atoms or an alkenyl group having 3 to 15 carbon atoms substituted at the 2- or 4-position, and furthermore, R1 is at the 2- or 4-position. A linear alkyl group having 5 to 8 carbon atoms, a branched alkyl group having 4 to 7 carbon atoms, or a 4-carbon alkyl group substituted at the 4-position
-8 alkenyl groups are more preferred, and most preferred R1 is a linear alkyl group having 6 to 7 carbon atoms, a 1-alkenyl group, or a branched alkyl group having 4 carbon atoms substituted at the 4-position.

R'' is a hydrogen atom or a linear or branched alkyl group having 1 to 3 carbon atoms. More preferably, R8 is a hydrogen atom or a methyl, ethyl, or n-purvyl group, and most preferably R8 is hydrogen. X is a linear or branched alkylene group having 1 to 3 carbon atoms, and more preferably X is a methylene group.

In addition, another aspect of the present invention has the general formula (n) (wherein, R' is substituted at the 2- to 4-position and has 4 to 1 carbon atoms.
5 linear, branched, or cyclic alkyl group or 3 carbon atoms
~15 alkenyl groups. ) is a 2°-hydroxychalcone derivative represented by formula (I), and is useful as an intermediate in the production of carfune derivatives represented by general formula (I). The method for producing the compound of the present invention is described below, and its outline is shown in Reaction Formula 1. Reaction formula 1 First, 2'-hydroxy-4'-(3-methyl-2-butenyloxy)acetophenone and The Journal Saibu
Saiichi Ganic Chemistry (J.Org.Che
m. ) Volume 49, Page 3963 (1984), Synthetic Communications (Syn.Com
mun. ) Vol. 13, p. 177 (1983) etc.
[) (In the formula, R1 and its position have the same meanings as above.

) is condensed with a benzaldehyde derivative represented by the formula (IF) in the presence of an alkali to produce a 2'-hydroxycarfune derivative represented by the general formula (IF).

Examples of the alkali used in this condensation reaction include potassium hydroxide, sodium hydroxide, sodium ethoxide, sodium methoxide, potassium t-butoxide, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate. As the reaction solvent, methanol, ethanol, n-probanol, inbrobanol, and t-butanol can be used alone or in combination with water.

The reaction temperature can be appropriately selected from O''C to the boiling point of the solvent used.

Next, a 2'-hydroxychalcone derivative represented by the general formula (IF) and the general formula (IV) Y-X-C O O R'' (IV)
(In the formula, R'' is an alkyl group having 1 to 3 carbon atoms, X has the same meaning as above, and Y represents 0!, Br+I, mesyl group or tosyl group.) By reacting a compound represented by General formula (I
) among the compounds represented by R! produces a compound in which is not a hydrogen atom.

The basic reagents used in this reaction include carbonate,
Sodium carbonate, sodium bicarbonate, potassium bicarbonate, potassium hydroxide, sodium hydroxide, sodium hydride, potassium hydride, sodium ethoxide, sodium methoxide, sodium amide, potassium amide,
Examples include n-butynorelithium, lithium diisopropinoleamide, potassium t-butoxide, and the like. As the reaction solvent, methanol, ethanol, n-propanol, isopropanol, acetone, dimethylformamide, dimethyl sulfoxide, benzene, toluene, tetrahydrofuran, dioxane, acetonitrile, chloroform, dichloromethane, etc. can be used. Further, a phase transfer catalyst or an iodine compound such as potassium iodide or sodium iodide can also be used as a reaction accelerator. The reaction temperature can be appropriately selected from -70°C to the boiling point of the solvent used.

Further, the compound represented by the general formula (I) in which R2 is a hydrogen atom can be produced by further hydrolysis.

This hydrolysis reaction produces potassium carbonate, sodium carbonate,
From O″C using an alkaline aqueous solution such as sodium bicarbonate, potassium bicarbonate, potassium hydroxide, or sodium hydroxide in an alcohol such as methanol, ethanol, n-probanol, or isoprobanol, or a solvent such as tetrahydrofuran or dioxane. It can be carried out appropriately within a temperature range up to the boiling point of the solvent.

Further, it is represented by the general formula (V) Y'-X-COOH (V) (wherein, X has the same meaning as above, and Y' represents 0?, Br.I, mesyl group or tosyl group). or its alkali salt represented by the general formula (n)
It can also be produced by reacting with a hydroxychalcone derivative.

Also, Reaction formula 2 outlines another method for producing the compound of the present invention.

Reaction Formula 2 (RI in Reaction Formula 2. R j and X are synonyms and are the same as above.

) [Effects of the Invention The chalcone derivative compound represented by the general formula (I) of the present invention has a strong antiulcer effect, a gastric mucosal protective effect, and an acid secretion suppressing effect. The chalcone derivative compounds of the present invention are useful, for example, in the treatment and prevention of gastrointestinal inflammatory diseases such as gastritis, gastric ulcers, duodenal ulcers, and the like.

Further, the chalcone derivative represented by the general formula (n) of the present invention is a compound useful as an intermediate for producing the chalcone derivative represented by the general formula (I>).

[Examples] The present invention will be explained in more detail below using Examples and Test Examples. Example 1 Production of 4-n-hexyl-2''-hydroxy-4'(3-methyl-2-butenyloxy)canolecone 6.60 g of 2'-hydroxy-4'-1(3-methyl-2-butenyloxy)acetophenone 5.70 g of 4-n-hexylbenzaldehyde was dissolved in 120 ml of isobrobyl alcohol, 25 mQ of 6N aqueous sodium hydroxide solution was added, and the mixture was reacted at 40°C for 8 hours. After the reaction was completed, the mixture was neutralized with dilute hydrochloric acid. The resulting solid was collected by filtration, washed with water, dried, and recrystallized from ethanol. Yellow needle-like crystals of 4-n-hexyl-2'-hydroxy-4゜(3
-Methyl-2-putenyloxy)carfune 7.72 g was obtained.

m. p. 7 4-75℃ MS m/z 2392 (M”).324.69IRv
2": cm-': 3440 (OH).2
927.1642(C=o)PMR(DMSO-da
) δ: 0. 86 (3H, t. J=7H2). 1
．． 28 (6H. a+). 1. 52-1. 65
(21. m>. 1. 73 (3H. s). 1.
76 (31.s). 2. 62 (2H.t.J=
8Hz). 4. 63 (2H.d.J=7Hz>.5.
44 (IH.t.J=7Hz>.6.51~6.58
(2H). 7. 29 (2H.d.J=8Hz>,
7.76-7, 84 (3H). 7.97 (IH.d.
J=15Hz), 8. 27 (IH.d.J=9Hz
), 13. 50 (11.s). Examples 2 to 1 1 The compounds shown in Table 1 were obtained in the same manner as in Example 1.0H Example 12 2'-monoethoxylponylmethoxy-4-n-hexyl-4'-(3-methyl-2- Preparation of 4-n-hexyl-2'-hydroxy-4'(3-methyl-2-butenyloxy) chalcone in 55 ml of dry acetone and pulverized potassium hydroxide 1
．． Added 4g. After stirring for 5 minutes, ethyl bromoacetate 2.
40 g was added and stirred at room temperature for 40 minutes. After the reaction was completed, dilute hydrochloric acid was added dropwise to neutralize the mixture while cooling with ice, and the precipitated solid was collected by filtration. After washing with water and drying, it was recrystallized from ethanol. Pale yellow needle crystals of 2゜ethoxycanolevoninolemethoxy-4-n-hexyl-4゜-(3-methyl-2
-butenyloxy) chalcone 5. 73g was obtained.

m. p. 56-57℃ MS m/z: 478 (M”), 410.69XRv
Two:: cm-': 2976.2929.17
63 (C=0), 1645 (C=0). 1608.15
7g. 1218.1185. PMR (DMSO-ds)
δ”0.85 (3H.t.J=7Hz).1.19
(3H.t.J=7Hz). 1. 21-1.31 (
6H, m), 1. 53-1. 60 (2H.m).
1. 73 (3H.s). 1. 76 (3H.
s). 2. 60 (2H.t.J=8Hz>, 4.
19 (2H.q.J”7Hz), 4. 61 (2H.q.J”7Hz).
d. J=7}1t). 5. 00 (2H.s). 5.
45 (IH.t.J=7HZ). 6. 65-6.
70 (2H.d, J=8Hz
). 7. 54-7. 68 (4｝1st part). 7.84
(LH, d.J=16Hz>. Examples 13 to 22 The compounds shown in Table 2 were obtained in the same manner as in Example 12. Example 23 2゜monolepoxymethoxy-4-n-hexynole-4
Preparation of '-(3-methyl-2-butenyloxy)chalcone 2'-1-Ethoxycanolevoninolemethoxy-4-n-hexyl-4゜-(3-methyl-2-butenyloxy)chalcone 4.30g was added to 43ml of ethanol. Dissolve, 6
．． Add 2g of potassium carbonate dissolved in 11mQ of water,
The mixture was stirred at 0°C for 5 hours. After the reaction was completed, the mixture was neutralized with dilute hydrochloric acid, and the precipitated solid was collected by filtration. After washing with water and drying, recrystallization was performed from a mixture of ethyl acetate and n-hexane to obtain 3.13 g of 2゜-carpoxymethoxy-4-n-hexyl-4゜-(3-methyl-2-butenyloxy) chalcone. .

m. p. 106~108℃MS m/z:
450(M”).69 IRν2::cm-':3429(C00H),292
g. 2858.1741 (C:O) 1647 (C=0)
．． 1607. 1578. 1249. 1023.
PMR(DMSO-da)S'0. 87(3
H. t. J=7Hz). 1. 20-1. 3
2 (6H.m)1. 51-1. 70 (2H,
m). 1. 75 (3H.s). 1. 77 (3H
．． s), 2. 61 (2H.t.J=7Hz>
, 4.63 (2H, d.J=7Hz), 4.92 (2H
．． s), 5. 45 (IH. t+ J”7Hz >.
6. 65-6. 70 (2H.m). 7. 24
<2H, d. J=8Hz), 7. 60 (LH.
J=16HZ), 7. 68 (LH, d. J=9H
z＞,7. 69 (2H. d. J: 8Hz), 7.
97 (IH.d.J=161{z). 13.28(
LH. s), Examples 24 to 36 The compounds shown in Table 3 were obtained in the same manner as in Example 23.

Example 37 Production of 2-n-heptyl-2′-hydroxy-4′(3-methyl-2-ptenyloxy)canolecone (1) 87.7 g of n-heptylbenzene was dissolved in 160 ml of nitroethane and 480 ml of dichloroethane. , anhydrous aluminum chloride 79. 5g was added in portions. Next, dichloromethyl methyl ether 54.

5 ml was dissolved in 60 td of dichloroethane and added dropwise.

After completion of the dropwise addition, the reaction mixture was further reacted for 1 hour at O''C, and then the reaction mixture was poured into ice water. After extraction with chloroform, washing with water and drying, the solvent was distilled off.

The residue was diluted with n-hexane:isopropyl ether (10:1).
) Silica gel chromatography fractionation was performed using the following solvent. 17.3 g of a colorless oily substance 2-heptylbenzaldehyde was obtained from the first two fractions that flowed out. A colorless oil, 4-heptylbenzaldehyde 64, was obtained from the fraction that flowed out later.
．． 8g was obtained.

(2) 2-heptylbenzaldehyde 3. llg and 2'-hydroxy-4'-(3-methyl-2-butenyloxy)acetophenone3. Dissolve 35 g in 65 mQ of isopropanol, and add 2 ml of sodium hydroxide under a nitrogen stream.
．． 9 g was dissolved in 6 mfL of water, added, and stirred at 45°C for 8 hours. The mixture was neutralized with dilute hydrochloric acid under water cooling, and extracted with ethyl acetate. After washing with water and drying, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column fractionation using n-hexane containing 1% ethyl acetate. The obtained target product fraction was recrystallized from inpropanol to give yellow needle-like crystals of 2-n-heptyl-
3.23 g of 2''-hydroxy-4''-(3-methynole-2-phtenyloxy)canolecone was obtained.

m. p. 65-67°C Example 38 2'-monocarpoxymethoxy-2-n-heptyl-4'-
(3-Methynole-2-putenyloxy) Production of kanolecon 60% oily sodium hydride 310μ DMF10
-2-n-heptyl-2'-hydroxy-4'-(3-methynole-2-putenyloxy') was suspended in mQ and cooled with water.
) 2.8 g of Kanolecon was dissolved in dry DMF10rd and added dropwise. Next, 1.2 g of ethyl bromoacetate was added, and the mixture was stirred at room temperature for 1 hour. After neutralizing with dilute sulfuric acid, the mixture was extracted with ethyl acetate. After washing with water and drying, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography using n-hexane containing 1% acetic acid ethyl ester, and the residue was purified by column chromatography using n-hexane containing 1% acetic acid ethyl ester.
There was 1.83 g of 2-n-heptyl-4'-(3-methyl-2-butenyloxy)canolecone. This is 30mQ
of ethanol and 10% potassium carbonate aqueous solution 15
ml was added and stirred at 60°C for 4.5 hours. The mixture was neutralized with dilute hydrochloric acid under water cooling, and the precipitated solid was collected by filtration and recrystallized from ethanol. 2゛-1-carpoxymethoxy-2-n-hebutyl-4゜-(3-methyl-2-
1.23 g of canolefun (butenyloxy) was obtained.

m. p. 118-121℃ MS m/z: 464(M”).297.6'!IRV
2,",'cm-': 3430 (COOH).
2922.2857.1759(C”0)1632(C
=O). 1605.1570,1543. PMR (DM
SO-ds) S'0.85 (3H.t.J=7Hz>,
1.24-1.29 (8H, m), 1.51 (2H.b
rs). 1.74 (3H, s). 1, 76 (31{.
s). 2. 74 (21.t.J=7Hz)
, 4.62 (2H.d.J=6Hz}, 4.92 (2H.d.J=6Hz}
．． ! ), 5. 44 (IH. t. J=6Hz).
6. 66-6. 71 (2H, m>.7.19~7
．． 37 (3H >. 7. 67 (IH, d.J=9
Hz), 7. 87-7. 91 (3H, m). 1
3. 28 (LH.s). Example 39 2゛1-kanoleboxymethoxy-4-n-heptyl-4'
Preparation of -(3-methyl-2-putenyloxy)carfun2'-carpoxymethoxy-4°-(3-methyl-2-
Butenyloxy)acetophenone 3. 48g and 4-n-
Heptylbenzaldehyde 2. 80g to 1 part ethanol
Dissolve in 20mQ, add 3.5g of potassium hydroxide,
The mixture was stirred for 50 minutes. It was neutralized with dilute sulfuric acid, and the precipitate was collected by filtration. After washing with water and drying, it was recrystallized from ethanol to give pale yellow needle-like crystals4. Obtained lOg. m. p. 106-107℃ MS m/z: 464 (M”).189.69IRv
2:: am-': 3467 (C00H). 29
55.2922.4740 (C=0), 1645 (C=
O). 1604,1498.1422.1252.11
83. PMR<DMSO-da>8'0. 85(
3}1, t, J”7Hz), 1.19 to 1.27
(8H.m). 1. 57 (2H.m). 1. 7
3 (3H.s). 1. 76 (3H.s). 2. 6
0 (2H.t, J=7Hz), 4. 62 (2H.
d. J=7Hz). 4. 90 (2H.S),
5. 44 (1B, t. .C7Hz). 6. 6
4-6. 69(2}1.m). 7. 23 (2H.
d. J=8Hz). 7. 59(1}1.d.J=
16H. ). 7. 67 (11. d. J=9Hz
). 7. 68 (2H.d.J=8Hz). 7
．． 96 (IH. d. JJ6Hz), 13. 27
(IH.s), Examples 40 and 41 In the same manner as in Example 39, the compounds shown in Table 4 were obtained.

Example 42 Preparation of 4-tert-butyl-2'-hydroxy-4-(3-methyl-2-butenyloxy)carfune 2'-hydroxy-4'-(3-methyl-2-butenyloxy)acetophenone54. 4g and 40.0g of 4-t-butylbenzaldehyde were dissolved in 1000ml of ethanol, 81.2g of potassium hydroxide was added, and the mixture was heated at 40°C.
The mixture was stirred for 9 hours. It was neutralized with dilute hydrochloric acid, and the precipitate was collected by filtration. After washing with water and drying, recrystallization from inpropanol yields a yellow powder of 4-t-butyl-2'hydroxy-4'-(3
-Methyl-2-putenyloxy) Kanorecon 47.6 g was obtained.

Example 43 Preparation of 4-t-butyl-2゜ethoxyluponinolemethoxy-4'-(3-methyl-2-butenyloxy)chalcone 4-t-Butyl-2'-hydroxy-4'(3-methyl- 45.1 g of 2-putenyloxy) kanolecone was dissolved in 500 mQ of acetone, 10.6 g of potassium hydroxide was added, and the mixture was stirred for 5 minutes. Furthermore, ethyl bromoacetate 21.5
g and stirred for 45 minutes. The mixture was neutralized with dilute hydrochloric acid, and the precipitated crystals were collected by filtration. After washing with water, drying, and recrystallizing from ethanol, a pale yellow powder of 4-t-butynole-2'-monoethoxyluponinolemethoxy-4'-(3-methynole-2
-butenyloxy)carfune 47.6 g were obtained.

m. p. 78-79°C Example 44 4-t-Petyl-2'-Canolepoxymethoxy4'-
Preparation of (3-methyl-2-butenyloxy)carfune 4-tert-butyl-2-ethoxylponylmethoxy-
4゜-(3-methyl-2-putenyloxy)chalcone 47
．． 3g of ethanol 600mQ G. : ? I understand,
Potassium carbonate29. 0 g was dissolved in 100 ml of water, added, and reacted at 45°C for 8 hours. Neutralize with dilute sulfuric acid,
The precipitated crystals were collected by filtration. After washing with water and drying, it was recrystallized with ethanol to obtain 29.9 g of 4-t-butyl-2'-carpoxymethoxy-4'(3-methyl-2-putenyloxy)carfune in the form of yellow needles. m. p. 136-139°C IRv2::cm-': 3430 (COOH).
2963.1753 (C=0). 1645 (C=O)
．． 1615, 1579. 1177. PMR (CD
a! m) S:l. 35 (9H, s). 1.78 (3H.
s). 1.83 (3H, s). 4.60 (2H.d.J
=7Hz). 4.79 (2H.s). 1. 83 (31
．． s). 4. 60 (2H, d, J=7Hz)
, 4. 79 (28.s). 5. 48 (IH.t
．． J=7Hz), 6. 57 (IH, d.J=2Hz)
．． 6.68<18. dd. J=9Hz. 2Hz). 7.
31 (IH.d.J=16Hz>.7.45 (2H
．． d. J=9HZ). 7. 58 (2H. d.
9Hz), 7.75 (IH.d, J=9Hz). 7.
81 (LH, d.J=16Hz>.Example 45 4-(t-butynole)-2'-(1-canolepoxyethoxy)-4'-(3-methyl-2-butenyloxy)
Production of canolefun (1) Suspend 4.0 g of sodium hydride in 40 ml of dimethylformamide, add 2'-hydroxy-4
'-(3-methyl-2-putenyloxy)acetophenone22. 0 g was dissolved in 10 mQ of dimethylformamide and added dropwise. Then, 18.5 g of 2-promobrobutylic acid ethyl ester was dissolved in dimethylformamide and added dropwise. After stirring at room temperature for 3 hours, the mixture was neutralized with dilute hydrochloric acid. After extraction with ethyl acetate, washing with water and drying, the solvent was distilled off to obtain 31.6 g of an oily substance. Dissolve this oil in 320 mQ of ethanol and add potassium R acid (40 g).
Aqueous solution 35ynQ was added and stirred at 70'C for 7 hours. After neutralizing with dilute hydrochloric acid, the mixture was extracted with ethyl acetate. washing with water,
After drying, the solvent was distilled off under reduced pressure, and the residue was recrystallized with Improvil ether to obtain 2°-(1-carpoxyethoxy)-4′-(3-methyl-2-butenyloxy)acetophenone as a white powder. 19.7g was obtained.

(21 2゜-(1-canoleboxyethoxy)-4゜-(3-methyl-2-putenyloxy)acetophenone 1.
1g and 4-(t-butyl)benzaldehyde 0.62
g, was dissolved in 20rd ethanol, and 0.g of potassium hydroxide was added. 84 g was added and stirred for 45 minutes. The mixture was neutralized with dilute hydrochloric acid and extracted with ethyl acetate. After washing with water and drying, the solvent was distilled off under reduced pressure, and the residue was mixed with n-hexane:ethyl acetate (10:1).
) After chromatography on silica gel with the mixed solution, recrystallization from benzene-10-hexane gave the title compound as a pale yellow powder. 91g was obtained.

m. p, 119-122°C Examples 46-48 The compounds shown in Table 5 were obtained in the same manner as in Example 45.
9 2゜lupoxymethoxy-4゜(3-methyl-2-
Preparation of (1-(E)butenyloxy)-4-(1-(E)one-cutenyl)carfun 15.7 g of terephthalaldehyde and 51.5 g of n-hepdeltriphenylphosphonium bromide were dissolved in 36 ml of dioxane, and 2,7+nQ water was added. Added. Furthermore, potassium carbonate32. 3 g was added and stirred vigorously under reflux. After 10 hours, the reaction solution was cooled and n-hexane was added. The precipitated crystals were filtered off, and the solvent was distilled off under reduced pressure. The remaining oil was subjected to silica gel chromatography fractionation using n-hexane containing 5% isobrobyl ether.
-21.9 g of (11-year-old ctenyl)benzaldehyde was obtained as an oil. (2゜lupoxymethoxy-4
9.35 g of 1-(3-methyl-2-butenyloxy)acetophenone, and 4-(11-ctenyl)benzaldehyde7. 37 g was dissolved in 170 ml of ethanol, 11.5 g of potassium hydroxide was added, and the mixture was stirred for 45 minutes.
The mixture was neutralized with dilute hydrochloric acid and the precipitated crystals were collected by filtration. Recrystallized from 90% ethanol to obtain the title compound 2'-1-canoleboxymethoxy-4-(3-methynole-2-butenyloxy)-4-(1-(E)1-year-old cutenyl) chalcone as a pale yellow powder. 9.2g was obtained. m. p. 103-105°C MS m/z: 476 (M”).69IRv,.
: cm-' : 3432 (COOH). 2925.
1746 (C=O). 1646 (C=O). PMR (DMSO-d.)6i:0. 87 (31
, t. J=7Hz>. 1.22~1.52 (8H.m
). 1.73 (38.d.J=IHz). 1.76 (3
H. s). 2.14-2.28 (2Lm), 4.62 (
2H. d, J=7Hz>. 4.91(2H,s>,5.
40-5.50 (LH, m). 6. 39-6.
44 (2H.m), 6. 64-6. 70 (2H
．． m). 7. 42 (2H.d.J=8Hz
). 7. 59 (LH. d. J=16Hz). 7
．． 68 (IH. d. .C8}1z>.7. 71
(2}1, d.J=8.Hz), 7. 98 (IH, d
．． ．． c16}1z). 13.26 (IH.s). Examples 50 to 52 The compounds shown in Table 6 were obtained in the same manner as in Example 49, and Example 5
3 Production of 2'-(1-canoleboxymethoxy)-4'(3-methyl-2-putenyloxy)-4-(4-pentenyl)carfun■ 970■ of magnesium was dissolved in 20m of tetrahydrofuran.
4-bromo-1-butene 5 to this suspension.
．． 20 mQ of 4 g of tetrahydrofuran solution was added dropwise while maintaining the temperature at 5,000. Subsequently, 20 mQ of a solution of 10.0 g of 4-promobenzyl bromide in tetrahydrofuran was slowly added dropwise. After refluxing for 1 hour, the mixture was acidified with dilute hydrochloric acid and extracted with n-hexane. After washing with water and drying, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography fractionation using n-hexane to obtain 1.14 g (7) 4-(4-pentenyl)bromobenzene.

(2) 4-(4-pentenyl)bromobenzene 1.13
g was dissolved in 20 ml of tetrahydrofuran, and 4.0 ml of a 1.5 mol n-hexane solution of n-butyllithium was added dropwise under dry ice-acetone cooling, followed by stirring for 15 minutes. Subsequently, 0.58 ml of dimethylformamide was added and stirred for 1 hour, then 50 TIIQ of water was added, extracted with ether, washed with water, dried, and the solvent was distilled off under reduced pressure to obtain 850 μ of 4-(4-bentenyl)benzaldehyde. Obtained. (3) 2'-(1-canoleboxymethoxy)-4'-(
3-Methyl-2-butenyloxy)acetophenone 1. L
2g. ! : 850 μl of 4-(4-pentenyl)benzaldehyde was dissolved in 15 ml of Improvil alcohol, 670 μl of potassium hydroxide was added, and the mixture was stirred for 15 minutes. The mixture was neutralized with dilute hydrochloric acid and extracted with ethyl acetate. washing with water,
After drying, the residue was evaporated under reduced pressure and the residue was recrystallized from ethyl acetate/n-hexane to obtain 920 ng of the title compound as a pale yellow powder.

m. p. 1 1 5 to 1 1 8°C Example 5
4-56 The compounds shown in Table 7 were obtained in the same manner as in Example 53.

Example 57 Production of 2゜-(1-carpoxymethoxy)-4'-(3-methyl-2-butenyloxy)-4-(2-brobenyl)carfun (υ4-promobenzaldehyde 27.75 g. Ethylene glyfur 12 g A catalytic amount of p-toluenesulfonic acid and p-toluenesulfonic acid were dissolved in benzene, and the mixture was refluxed for 2 hours using a Utera separator.The solvent was distilled off under reduced pressure, and the residue was distilled under reduced pressure to obtain 2-(4-butyl Mophenil)
27.9 g of -r, s-dioxyxotene was obtained. (486 ml of magnesium was suspended in 20 ml of tetrahydrofuran, and 40 ml of a solution of 4.58 g of 2-(4-promophenyl)-1,3-dioxolane in tetrahydrofuran was added dropwise to the suspension while maintaining the temperature at 50°C. Subsequently, 20 ml of a solution of 4.84 g of allyl bromide in tetrahydrofuran was slowly added dropwise, and after refluxing for 1 hour, the mixture was treated with dilute hydrochloric acid and extracted with ether.The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. Thereafter, the solvent was distilled off under reduced pressure, and the residue was fractionated using silica gel column chromatography using a mixed solvent of ether:n-hexane (1:100) to obtain 900 mg of 4-(2-propenyl)benzaldehyde.

■) 2'-(1-carpoxymethoxy)-4'(3-methyl-2-putenyloxy)acetophenone 834mg 4-(2-propenyl)benzaldehyde 500
(2) was dissolved in ethanol IOTIII, 842 (842) potassium hydroxide was added, and the mixture was stirred for 20 minutes. The mixture was neutralized with dilute hydrochloric acid and extracted with ethyl acetate. After washing with water and drying, distill it off under reduced pressure.
The residue was recrystallized from ethyl acetate/n-hexane to obtain the title compound 645 as pale yellow needles. m. p. 1 2 5-126°C Test Example 1 Stress Ulcer Suppression Effect Test (Sample) Compounds obtained in Examples with the same sample numbers as the sample numbers shown in Table 8 were used as the samples.

In addition, the following compounds A to E were used as control compounds.

A: 4-kanolepoxy 2'-kanoleboxymethoxy-
4'-(3-methyl-2-butenyloxy)kanolecon B: 2',4-bis(carboxymethoxy)-4°-(
3-methynole-2-butenyloxy)kanolecon C: 2'-monolepoxymethoxy-4,4'-bis(3
-methynole-2-butenyloxy)chalcone D: 2'monolupoxymethoxy4-methyl-4'-(3-methyl-
2-butenyloxy) carfun E: 2'-monocarpoxymethoxy-4'-(3-methyl-
2-Ptenyloxy)-4-n-propylene (Test method) K. Takagi et al. Japan J. Phar
macol. ．． Volume 18. A stress ulcer inhibitory effect test was conducted according to the method described on page 9 (1968).

That is, 0.42 CMC was given to male Wistar rats (7 rats per group) weighing 160 to 180 g that had been fasted for 24 hours.
Test drug (50 μ/kg to 10 μg/kg) prepared by suspending in
0+yg/kg) was orally administered, placed in a wire mesh gauge for stress loading, immersed in a constant temperature bath at 23°C to below the sternum, and
After a period of time, the abdomen was opened and the area of erosion occurring in the stomach body was measured, and the inhibition rate was calculated.

(result) The results are shown in Table 8.

Table 8 Test Example 2 Gastric Mucosa Protective Effect Test (Sample) Compounds obtained in Examples with the same sample numbers as the sample numbers shown in Table 9 were used as the samples. In addition, as control compounds, the same compounds A to E as in Test Example 1 were used.

(Test method) A. Gastoenterolog of Robert et al.
By the method described in Vol. 77, pp. 433-443 (1979). A 0.6N-hydrochloric acid-induced gastric disorder (gastric mucosal protective effect) test was conducted.

That is, 7 male Wistar rats per group (body weight 1
80-210 g) were fasted for 24 hours. The dose of the drug prepared by suspending it in 0.4% CMC (
50 μ/kg to 100 μ/kg) was administered orally.

After standing at room temperature for 2 hours, 1 mQ/rat of 0.6N monohydrochloric acid was orally administered. After being left at room temperature for an additional hour, the rats were sacrificed, and the length of the gastric mucosal lesions developed in the gastric body was measured, and the sum total was taken as the lesion coefficient per rat. The lesion coefficient of the drug administration group was compared with the lesion coefficient of the non-administration group, and the inhibition rate was calculated.

(result) The results are shown in Table 9.

Table 9 Test Example 3 Gastric acid secretion inhibition test by intragastric perfusion method (sample) Sample 1: Compound control sample of Example 44 = 2'-monocarboxymethoxy-4,4'-bis(3-methyl-2-putenyloxy) carfun ( Test method) K. European Journal of Watanbe et al.
Talented Pharmacology (Eur. J. Phar
Macology) Volume 90, Pages 11-17 (1
A gastric acid secretion suppression test was conducted using the intragastric perfusion method according to the method described in 1983).

That is, Wista rats (4 rats per group) weighing 300 to 350 g that had been fasted for 18 hours were treated with urethane (1.25 g).
/ kg, s. c. ) The abdomen was opened under anesthesia, and gastric perfusate cannulas were inserted into the stomach from the anterior dorsal and duodenal regions.The gastric perfusate was physiological. Using a saline solution, inject it into the stomach through the cannula in the forestomach region using a Verisbump, sample the perfusate flowing out from the cannula in the duodenum region at 5-minute intervals, and use a 0.02N aqueous sodium hydroxide solution to infuse the perfusion fluid into the stomach. { Measured with stat (end point pH 7.0) L, the amount of secreted acid was measured. The stimulation of acid secretion is stimulated by 2-deoxyD-glucose (20
0mg/kg, s. c, ) and indomethacin (20 mg/kg, s.c.);
80 minutes after administration, the sample was suspended in a 5% gum arabic aqueous solution and administered intraperitoneally, the amount of gastric acid secretion was measured for 5 hours, and the gastric acid secretion suppression rate was calculated from that of the control group (only 5% aqueous gum arabic solution was administered). did. (Results) The results are shown in Table 10. Table 10

Claims (1)

[Claims] 1) General formula ▲ Numerical formula, chemical formula, table, etc.
15 linear, branched, or cyclic alkyl group or alkenyl group having 3 to 15 carbon atoms, R^2 is a hydrogen atom, a linear or branched alkyl group having 1 to 3 carbon atoms, represents a linear or branched alkylene group having 1 to 3 carbon atoms. ) is a chalcone derivative represented by ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 is a carbon number of 4 to 4 substituted at the 2nd or 4th position
15 linear, branched, or cyclic alkyl groups or alkenyl groups having 3 to 15 carbon atoms. ) 2'-
Hydroxychalcone derivative.